An immune response occurs only if a T lymphocyte has been able to recognize the foreign antigen in association with a self molecule encoded by the major histocompatibility complex (MHC). These molecules expressed on antigen-presenting cells are the polymorphic class II MHC antigens. Most foreign antigens must be processed in order to bind to MHC molecules. Antigen processing for presentation by class II molecules generally involves endocytosis of antigen into an acidic compartment through which newly synthesized class II molecules are passing on their way to the cell surface. Once at the cell surface, the foreign peptide/MHC class II complex interacts with the T cell receptor and the CD4 molecule expressed on the antigen-specific T cell. The aim of this project is to define the function of human class II molecules in their interaction with T cells and the requirements for class II-restricted processing and presentation of viral antigens to CD4-positive T cells. It has been demonstrated that a cytosolic antigen was endogenously processed in infected cells for class II-mediated presentation. Most interestingly, the processing pathway involved was different from the one utilized for presentation by class I molecules. This unsuspected presentation of endogenous proteins by class II molecules has important implications on the T cell repertoire selection, on T cell tolerance, and on autoimmunity. HLA-DP and HLA-DR are two isotypes of human class II molecules with distinct alpha and beta chains. To define what determines alpha/beta chain assembly, chimeric alpha and beta chains were expressed in a transient expression system. The data showed that the lack of mixed isotype expression was due to a lack of intracellular pairing, and that DP and DR molecules had distinct structural requirements for pairing. Several staphylococcal toxins bind to class II molecules and have a strong mitogenic effect on T cells stimulating families of T cells with particular V-beta chains of the TCR. Using a direct binding assay and chimeric DP/DR molecules expressed by transient tranfection, it was shown that the toxic shock syndrome toxin does not bind detectably to the DP molecule and that the alpha1 domain of DR is essential for high affinity binding.